New cationic amphiphilic compounds as potential antibacterial agents Visser, Peter Christian de

New cationic amphiphilic compounds as potential antibacterial agents

Visser, Peter Christian de

Citation

Visser, P. C. de. (2006, February 23). New cationic amphiphilic compounds as potential

antibacterial agents. Retrieved from https://hdl.handle.net/1887/4335

Version:

Corrected Publisher’s Version

License:

Licence agreement concerning inclusion of doctoral thesis in the

_{Institutional Repository of the University of Leiden}

Downloaded from:

https://hdl.handle.net/1887/4335

New Cationic Amphiphilic Compounds

as Potential Antibacterial Agents

PROEFSCHRIFT

ter verkrijging van

de graad van Doctor aan de Universiteit Leiden,

op gezag van de Rector M agnificus Dr. D.D. Breim er,

hoogleraar aan de faculteit der W iskunde en

Natuurwetenschappen en die der Geneeskunde,

volgens het besluit van het College voor Prom oties

te verdedigen op donderdag 23 februari 2006

te klokke 16:15 uur

door

Pet

er Chri

st

i

an de Vi

sser

Promotiecommissie

Promotor

:

Prof. dr. H.S. Overkleeft

Co-promotor :

Dr. D. Noort (TNO Defensie & Veiligheid)

Referent

:

Dr. M. Overhand

Overige leden :

Prof. dr. J. Lugtenburg

Prof. dr. A. van der Gen

Prof. dr. G.A. van der Marel

Prof. dr. J. Brouwer

Dr. D.V. Filippov

Dr. P.A.V. van Hooft (TNO Defensie & Veiligheid)

The research described in this thesis was conducted at the Bioorganic Synthesis (BIOSYN) department of the Leiden Institute of Chemistry (LIC, Leiden University) in cooperation with and financed by TNO.

Printed by Optima Grafische Communicatie, Rotterdam, 2006

in memoriam prof. dr. Jacques H. van Boom

If we knew what it was we were doing, it would not be called research, would it?

- Albert Einstein (1879-1955)

Table of Contents

Table of Contents

List of Abbrevations

G eneral Introduction

Chapter 1

Biological Evaluation of Stabilized Drosocin Analogues

Chapter 2

Safety-Catch Synthesis & Biological Evaluation of Polymyxin B1 and Analogues

Chapter 3

Acyl M igration in Polymyxin Synthesis

Chapter 4

Design, Synthesis & Biological Evaluation of PM BN/CAP Conjugates

Chapter 5

Table of Contents

Chapter 6

Fluorous Techniques in Solid-Phase Peptide Synthesis

Chapter 7

Summary & Future Prospects

General M aterials & M ethods

Samenvatting

Summary in Dutch

List of Publications

Curriculum V itae

List of Abbreviations

6

List of Abbreviations

a C-terminal amide AA amino acid residue1 Abu DŽ-aminobutyric acid Ac acetyl

ACPC trans-2-aminocyclopentane carboxylic acid

Ada 1-adamantaneacetyl ADP adenosine 5’-diphosphate Ala (A) alanine

AM aminomethyl anh. anhydrous aq. aqueous Ar aromatic Arg (R) arginine Asn (N) asparagine Asp (D) aspartic acid AP alkaline phosphatase ATCC American type culture

collection

Ava Dž-aminovaleric acid2

ǃAla ǃ-alanine BF2 buforin II

BHI brain/heart infusion bm broad multiplet Bn benzyl Boc tert.-butoxycarbonyl BOP (benzotriazol-1-yloxy)tris- (dimethylamino)phosphonium hexafluorophosphate Bu butyl c (prefix) cyclo

Cx n-alkyl chain containing x

carbon atoms

CAP cationic antimicrobial peptide Capro (S)-3-amino-1-carboxymethyl

caprolactame CD circular dichroism CFU colony-forming units Clt (2-chlorotriphenyl)methyl CMP cytidine 5’-monophosphate Cmpi N-carboxymethylpiperazine COSY correlated spectroscopy CPC cetylpyridinium chloride

1 _{W here applicable, am ino acid residues are of the L}

-configuration unless otherw ise stated.

2 _{D ue to shortage of unique one-letter codes, Ava is}

denoted w ith X in C hapter 4 and Tm d(Phe) w ith Z in C hapter 7.

CPMBN Cys-polymyxin B nonapeptide CTAB cetyltrimethylammonium

bromide Cys (C) cysteine

Dab (X) ǂ,DŽ-diaminobutyric acid2 dansyl 5-dimethylamino-1-naphthalenesulfonyl DAST diethylaminosulfurtrifluoride DCC N,N’-dicyclohexylcarbodiimide DCE 1,2-dichloroethane Dde 1-(4,4-dimethyl-2,6-dioxo- cyclohex-1-ylidene)ethyl Dhb (U) ǂ-aminodehydrobutyric acid DIAD diisoproyl azodicarboxylate DiBAl-H diisobutylaluminum hydride DIC N,N’-diisopropylcarbodiimide DiPEA N,N-diisopropylethylamine DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide DMSO dimethylsulfoxide DNA deoxyribonucleic acid DOSPER

1,3-dioleyloxy-2-(6-carboxy-spermidyl)propylamide DPPA diphenylphosphoryl azide DPX dansylated polymyxin B DRC (S7T)-drosocin DTT dithiothreitol EDC N-(3-dimethylaminopropyl)-NĻ-ethylcarbodiimide EDTA ethylenediaminetetraacetate ESI electrospray interface

Et ethyl

eq. equivalent(s)

E-gel gel containing ethylene glycol F (prefix) fluorous

FA or fa fatty acyl

FDA (United States) Federal Drug Administration

FITC fluoresceinyl isothiocyanate Fmoc 9-fluorenylmethoxycarbonyl Gal galactose G_ Gram-negative G+ _{Gram-positive} Glc glucose Gln (Q) glutamine Glu (E) glutamic acid Gly (G) glycine

List of Abbreviations

7

G-gel gel containing glycerol HATU O-(7-azabenzotriazol-1-yl)-N,N,NĻ,NĻ-tetramethyluronium hexafluorophosphate hBD human ǃ-defensin HCTU O-(6-chlorobenzotriazol-1-yl)-N,N,NĻ,NĻ-tetramethyluronium hexafluorophosphate

Hep L-glycero-D-manno-heptose HEPES N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) His (H) histidine HMDS hexamethyldisilazane HOAt 1-hydroxy-7-azabenzotriazole HOBt 1-hydroxybenzotriazole HPLC high-performance liquid chromatography HRMS high-resolution mass spectrometry HSer (ǃ_{S) ǃ}3_-homoserine HTyr (ǃY) ǃ3-homotyrosine

IBX triacetoxyiodobenzoic acid IL interleukin

Ile (I) isoleucine

IM inner (cytoplasmic) membrane IR infrared

ISB iso-sensitest broth

ISO International Organization for Standardization

ivDde 1-(4,4-dimethyl-2,6-dioxocyclo- hex-1-ylidene)-3-methylbutyl Kdo 3-deoxy-D

-manno-oct-2-ulosonic acid KFF KFF peptide (KFF)3K LB Luria-Bertani (broth) LBP LPS-binding protein LC liquid chromatography LCMS liquid chromatography/mass spectrometry Leu (L) leucine LPS lipopolysaccharide Lys (K) lysine OM outer membrane Orn (O) ornithine

Mamb m-(aminomethyl)benzoic acid MALDI matrix-assisted laser

desorption/ionisation Me methyl Me_{Arg (}Me_{R) N}ǂ_{-methylarginine} Me_{Ser (}Me_{S) N-methylserine} Met (M) methionine MHC minimal hemolytic concentration

MIC minimal inhibitory

concentration, i.e. the lowest concentration at which no bacterial growth can be detected by spectroscopic analysis after incubation for a specified time, compared with a positive control (Triton X-100).

MIM N-methyl-N’-alkyl imidazolium

MMT (4-methoxytriphenyl)methyl MOA (S)-6-methyloctanoyl, -oic acid Mpa 3-maleimidopropionyl MPD

N-methyl-N-alkyl-pyrrolidinium MS mass spectrometry MS/MS tandem mass spectrometry Msc methylsulfonylethoxycarbonyl Mtt (4-methyltriphenyl)methyl MW microwave (oven) n (prefix) natural

n- normal (linear) n/a not applicable n/d not determined NBE nutrient broth E NCL native chemical ligation nG not glycosylated NMP N-methylpyrrolidone NMR nuclear magnetic resonance NOE nuclear Overhauser effect NOESY nuclear Overhauser effect

spectroscopy Orn (O) ornithine

Pamb p-(aminomethyl)benzoic acid PAMP pathogen-associated molecular

List of Abbreviations

8

PyBroP bromotripyrrolidino- phosphonium hexafluorophosphate QAC quaternary ammonium

compound RBC red blood cell Ref. reference Rf retardation factor

RNA ribonucleic acid ROESY rotating frame NOESY RP reversed phase Rt retention time RT room temperature RTD rhesus lj-defensin s (prefix) synthetic

SAA sugar amino acid Sar sarcosine sat. saturated

SCL 3-carboxypropanesulfonamide Ser (S) serine

SIC streptococcal inhibitor of complement

SPE solid-phase extraction SPPS solid-phase peptide synthesis SPy 2-pyridylsulfenyl

SS disulfide linkage StBu tert.butylsulfenyl Su succinimidyl tBu tert.butyl

TCA trichloroacetic acid

TCEP tris(carboxyethyl)phoshine TES triethylsilane

TFA trifluoroacetic acid TFE 2,2,2-trifluoroethanol THF tetrahydrofuran THP tetrahydropyran Thr (T) threonine TIC total ion count TIS triisopropylsilane Tmd 3-(trifluoromethyl)-3H-diazirin-3-yl TMS trimethylsilyl TNBS 2,4,6-trinitrobenzenesulfonic acid

TNF tumor necrosis factor TLC thin-layer chromatography TLR Toll-like receptor

TOCSY total correlation spectroscopy TOF time-of-flight

Tr triphenylmethyl Tran tranexamic acid Trp (W) tryptophane TTC tritrpticin Tyr (Y) tyrosine

UDP uridine 5’-diphosphate UV ultraviolet

Val (V) valine